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Biomedical subjects

A Raz

Publications and source records attributed to A Raz.

At least 73 records · Page 4Linked to original sources
PubMed1998

Metastasis of human colon cancer is altered by modifying expression of the beta-galactoside-binding protein galectin 3.

BACKGROUND & AIMS: Galectin 3 is a beta-galactoside-binding protein whose expression has been correlated with advanced tumor stage in the colon, but direct evidence for a role in metastasis is lacking. The current study was designed to more directly establish the role of galectin 3 in colon cancer metastasis. METHODS: Galectin 3 levels were manipulated in human colon cancer cells using eukaryotic expression constructs designed to express the complete galectin 3 complementary DNA in either the sense or antisense orientation. Liver colonization was assessed in athymic mice after splenic-portal inoculation or after spontaneous metastasis during cecal growth. RESULTS: Introduction of galectin 3 antisense into metastatic colon cancer cells (LSLiM6, HM7) resulted in a significant reduction in galectin 3-specific messenger RNA and total and cell surface galectin 3 protein. Conversely, stable integration of galectin 3 in the sense orientation resulted in an increase in cellular and cell surface galectin 3 in cells of low metastatic potential (LS174T). Reduction in galectin 3 levels was associated with a marked decrease in liver colonization and spontaneous metastasis by LSLiM6 and HM7 cells, whereas up-regulation of galectin 3 resulted in increased metastasis by LS174T cells. CONCLUSIONS: This study provides direct evidence that galectin 3 plays an important role in colon cancer metastasis.

Adenocarcinoma↗
PubMed1998

Physiological aspects of information processing in the basal ganglia of normal and parkinsonian primates.

There are two views as to the character of basal-ganglia processing - processing by segregated parallel circuits or by information sharing. To distinguish between these views, we studied the simultaneous activity of neurons in the output stage of the basal ganglia with cross-correlation techniques. The firing of neurons in the globus pallidus of normal monkeys is almost always uncorrelated. However, after dopamine depletion and induction of parkinsonism by treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), oscillatory activity appeared and the firing of many neurons became correlated. We conclude that the normal dopaminergic system supports segregation of the functional subcircuits of the basal ganglia, and that a breakdown of this independent processing is a hallmark of Parkinson's disease.

Animals↗
PubMed1998

Galectin-3 and L1 retrotransposons in human breast carcinomas.

Galectin-3 is a galactoside binding protein found at elevated levels in a wide variety of neoplastic cells and thought to be involved in cognitive cellular interactions during transformation and metastasis. Previously, we have shown that introduction of human galectin-3 (Mr 31,000) cDNA into the human breast cancer cells BT-549 which are galectin-3 null and non-tumorigenic in nude mice resulted in the establishment of four galectin-3 expressing clones. Three of them acquired tumorigenicity when inoculated in the mammary fat pad of nude mice. Here, we questioned what is the molecular difference between the nude mouse tumorigenic and non-tumorigenic galectin-3 expressing BT-549 cell clones. Differential display analysis and Northern blotting revealed that, unlike the tumorigenic clones, neither the parental cells nor the non-tumorigenic clone expressed a 6.5 Kb transcript. A 607 bp PCR (polymerase chain reaction) product from the differentially displayed mRNA revealed a 93% sequence homology with the human L1 retrotransposon previously suggested to play a role in the pathobiology of some breast cancers. In addition, we show that the two gene products, i.e., galectin-3 and L1, are co-expressed in breast carcinoma specimens and in other nude mouse tumorigenic cell lines.

Antigens, Differentiation↗
PubMed1998

Preservation of fertility in women undergoing chemotherapy: current approach and future prospects.

PURPOSE: Anticancer treatment causes ovarian failure. METHODS: Some hormones may have a protective effect on the ovary. Cryopreservation (freezing) of oocytes has had very limited success, and therefore, currently its use before chemotherapy is not a feasible option. However, cryopreservation of embryos is possible. Another solution is oocyte donation followed by in vitro fertilization (IVF). RESULTS: Ovarian cortical slices containing primordial follicles have been cryopreserved successfully. To restore fertility, cryopreserved-thawed tissue taken from cancer patients before therapy could be replanted after recovery. The possible risk of malignancy restoration could be eliminated by obtaining unilaminar follicles from cryopreserved-thawed tissue and growing them in vitro, followed by routine IVF. CONCLUSIONS: Although women who undergo chemotherapy face limited options for fertility preservation, intensive studies in cryopreservation and in vitro maturation of follicles harbor hope for brighter prospects in the future.

Age Factors↗
PubMed1998

Activated protein C resistance in pediatric inflammatory bowel disease.

BACKGROUND: There is evidence for a hypercoagulable state in inflammatory bowel disease (IBD), and small vessel thrombosis has been identified in the bowel of patients with Crohn's disease, suggesting thrombosis as a possible etiologic factor. Activated protein C (APC) resistance is the most common inherited disorder leading to thrombosis and accounts for 30% to 40% of episodes of idiopathic venous thrombosis. METHODS: The prevalence of APC resistance was studied in 23 patients with IBD (17 with Crohn's disease, 6 with ulcerative colitis) and in 11 control subjects with recurrent abdominal pain or celiac disease, using an APC resistance screening method. RESULTS: One patient with Crohn's disease had a positive screen result, two patients (one with Crohn's, one with ulcerative colitis) had borderline results, and results in all of the control subjects were normal. One patient with Crohn's disease had a history of a thromboembolic event but had a normal screen result. CONCLUSIONS: Activated protein C resistance does not seem to play a major role in the etiology of the hypercoagulable state in inflammatory bowel disease.

Adolescent↗
PubMed1998

Autocrine motility factor in pulmonary adenocarcinomas: results of an immunohistochemical study.

Autocrine motility factors (AMF) have been shown to play an important role in tumor cell migration and metastasis. We have detected AMF expression in tissue specimens from 119 patients with pulmonary adenocarcinoma and examined the relationship between AMF expression, clinicopathological factors and prognosis. AMF expression was correlated with lymph node metastasis and stage. The prognosis of AMF-positive patients was poorer than that of AMF-negative patients. The expression of AMF correlated with more tumor aggressiveness and worse prognosis in pulmonary adenocarcinomas.

Adenocarcinoma↗
PubMed1998

Novel, selective delta6 or delta5 fatty acid desaturase inhibitors as antiinflammatory agents in mice.

Decreased synthesis of arachidonic acid by inhibition of the Delta6 or Delta5 desaturase was evaluated as a means to mitigate inflammation. Using quantitative in vitro and in vivo radioassays, novel compounds representing five classes of Delta5 desaturase inhibitors and one class of Delta6 desaturase inhibitor were identified. The Delta6 desaturase inhibitor, SC-26196, had pharmacokinetic and pharmacodynamic profiles in mice that allowed for the evaluation of the pharmacological effects of chronic inhibition of desaturase activity. SC-26196 decreased edema to the same extent as indomethacin or essential fatty acid deficiency in the carrageenan paw edema model in the mouse. The antiinflammatory properties of SC-26196 were consistent with its mechanism of action as a Delta6 desaturase inhibitor: 1) A correlation existed between inhibition of liver Delta6 desaturase activity and decreases in edema. 2) The onset of the decrease in edema was time dependent. 3) Selective reduction of arachidonic acid occurred dose dependently in liver, plasma and peritoneal cells. 4) In the presence of SC-26196, controlled refeeding of arachidonic acid, but not oleic acid, reversed the changes resulting from desaturase inhibition. The Delta6 desaturase may be a target for development of antiinflammatory drugs whose mechanism of action is unique.

Animals↗
PubMed1997

Galectin-3: a novel antiapoptotic molecule with a functional BH1 (NWGR) domain of Bcl-2 family.

Galectin-3, a beta-galactoside-binding protein, has been shown to be involved in tumor progression and metastasis. Here, we demonstrate that expression of galectin-3 in human breast carcinoma BT549 cells inhibits cis-diamminedichloroplatinum (cisplatin)-induced poly(ADP-ribose) polymerase degradation and apoptosis, without altering Bcl-2, Bcl-X(L), or Bax expressions. Galectin-3 contains the NWGR amino acid sequence highly conserved in the BH1 domain of the bcl-2 gene family, and a substitution of glycine to alanine in this motif abrogated its antiapoptotic activity. Our findings demonstrate that galectin-3 inhibits apoptosis through a cysteine protease pathway and highlight the functional significance of the NWGR motif in apoptosis resistance of a non-Bcl-2 protein.

Amino Acid Sequence↗
PubMed1997

Expression of the endogenous galactose-binding protein galectin-3 correlates with the malignant potential of tumors in the central nervous system.

BACKGROUND: The 31-kilodalton beta-galactoside-binding protein galectin-3 has been associated with cellular transformation and metastasis. Because neural tissues contain large amounts of glycoconjugates, and endogenous carbohydrate-binding proteins have been described in the human brain, the authors examined the expression of galectin-3 in human brain tumors and metastases to the central nervous system. METHODS: Brain tumors were categorized by the World Health Organization system and galectin-3 expression by immunoperoxidase staining using a quantitative staining score. RESULTS: Glioblastomas (Grade 4 astrocytomas) all stained strongly for galectin-3, whereas low grade astrocytomas (Grade 2) did not express the endogenous lectin. Anaplastic astrocytomas (Grade 3) exhibited intermediate expression. The staining score was significantly associated with tumor grade (P < 0.001). Normal brain tissue and benign tumors did not express galectin-3, whereas metastases to the brain were all positive for galectin-3 expression. Metastases expressed significantly more galectin-3 than the primary tumors from which they were derived (P = 0.003). CONCLUSIONS: Galectin-3 expression correlates with the malignant potential of tumors in the central nervous system.

Antigens, Differentiation↗
PubMed1997

Modulation of adjuvant-induced arthritis by dietary arachidonic acid in essential fatty acid-deficient rats.

Controlled feeding of linoleic acid (LA) or arachidonic acid (AA) to essential fatty acid-deficient (EFAD) rats was used to define the relationship between dietary AA and the inflammatory response evoked during adjuvant-induced arthritis. Based on energy percentage, EFAD rats were fed AA at the human daily equivalent (1x; 5.5 mg/day) or 10 times that amount (10x; 55 mg/day) or, alternatively 0.5x of LA (273 mg/day). Feeding of 0.5x LA restored the plasma level of AA to that in chow-fed controls. In contrast, feeding of 1x AA only partially restored the plasma level of AA; 10x AA was required to fully replete AA. In parallel to the degree of repletion of AA in plasma, there were accompanying decreases in the levels of palmitoleic acid, oleic acid, and Mead acid. Compared to rats fed the standard laboratory chow diet (Control), edema in the primary hind footpads was decreased by 87% in EFAD, 71% in EFAD + 1x AA, 45% in EFAD + 10x AA, and 30% in EFAD + 0.5x LA. The decrease in edema in the footpads of EFAD rats was nearly identical to the decrease in edema in the footpads of Control rats dosed with indomethacin. Hind footpad edema correlated with the final AA plasma level and eicosanoid levels extracted from hind footpad tissue, but not with neutrophil infiltration. The data showed that 0.5x LA and 10x AA, but not 1x AA, could quickly replete AA, accompanied by the synthesis of AA-derived eicosanoids and restoration of edema. These results suggest that in humans consumption of the average daily amount of AA without concurrent ingestion of LA would not alleviate an EFAD state.

Animals↗
PubMed1997

Improved prognosis assessment for patients with bladder carcinoma.

Urothelial carcinomas are heterogeneous diseases with an aggressive clinical potential. To date, the most used prognostic factors for bladder carcinomas are grade and stage, which are based on histopathological parameters that are often not reliable in predicting a clinical outcome. Here, we evaluated the clinical outcome of 100 patients with urothelial carcinomas with follow-up information for more than 2 years after surgery in relation to the expression of two cell surface antigens, ie, E-cadherin and autocrine motility factor receptor (AMF-R, gp78). Frozen bladder tissues were serially cut, stained either with hematoxylin and eosin for grading, with the anti-gp78 antibodies, or with anti-E-cadherin antibodies to determine level of expression. Of 63 patients presented at the time of diagnosis with pathological loss of E-cadherin associated with increased gp78 expression, 39 (62%) succumbed to tumor progression or death. Of 37 patients with normal E-cadherin and gp78 expression positive and negative, respectively, 36 (97%) had favorable disease outcomes (P < 0.0001). The results suggest that in bladder carcinomas abnormal expression of both E-cadherin and gp78 results in a poor disease outcome, independent of tumor stage and grade.

Age Factors↗
PubMed1997

Adhesion of human breast carcinoma to extracellular matrix proteins is modulated by galectin-3.

In this report, we have analyzed the adhesive interactions of a breast carcinoma cell line, BT-549, and its galectin-3-transfected subclone 11-9-1-4 with laminin, collagen IV and fibronectin. We determined that 11-9-1-4 cells adhered much more rapidly (within 1 h of plating) to laminin- and collagen IV-coated wells than the galectin-3 null expressing BT-549 cells. However, after 24 h, both cell lines fully adhered to laminin and collagen IV. Both cell lines also achieved maximum adhesion to fibronectin within 30 min. Not only did 11-9-1-4 express galectin-3 in the usual punctate pattern on its cell surface, it demonstrated a higher surface expression of alpha 6 beta 1 integrin compared to BT-549. The 11-9-1-4 cells were able to invade through matrigel-coated polycarbonate filters at approximately 3 times the rate of BT-549 parental cells. Our data suggest that galectin-3 is essential for adhesion to laminin and collagen IV but not fibronectin by breast carcinoma cells. In addition, galectin-3 expression may modulate the surface expression of some of the integrins specific for laminin and collagen IV adhesion and invasion of basement membrane by breast carcinoma cells.

Antigens, Differentiation↗
PubMed1996

Carbohydrate-mediated regulation of matrix metalloproteinase-2 activation in normal human fibroblasts and fibrosarcoma cells.

Matrix metalloproteinase-2 (MMP-2) is activated on the cell surface by membrane type 1-MMP (MT1-MMP). Activation of proMMP-2 is induced in vitro by concanavalin A (ConA). The regulation of proMMP-2 activation is, however, not yet fully understood. We investigated the effect of plant lectins, carbohydrates and inhibitors of the cytoskeleton on proMMP-2 activation in normal (HLF1) and malignant fibroblast (HT1080) cells. Native ConA induced proMMP-2 activation in both cell types while dimeric succinyl-ConA had no effect, suggesting that receptor clustering is involved in activation. Wheat germ agglutinin (WGA) also induced proMMP-2 activation. N-acetyl-D-glucosamine (GlcNac) inhibited the effects of ConA and WGA while mannose only inhibited ConA-induced proMMP-2 activation. Mannose also inhibited the expression of MT1-MMP mRNA induced by ConA. Cytochalasin B and colchicine had no effect on the ConA induction of proMMP-2 activation. These studies help to define some of the cellular and molecular mechanisms for the induction of proMMP-2 activation.

Acetylgalactosamine↗
PubMed1996

Colon cancer mucin: a new ligand for the beta-galactoside-binding protein galectin-3.

Galectin-3, an endogenous beta-galactoside-binding lectin, is present on colon cancer cells and may play a role in metastasis. Galectin-3 binds poly-N-acetyllactosamine structures on glycoproteins, but its natural ligands remain to be fully defined. Galectin-3 bound to purified native and desialylated colon cancer mucin in a concentration-dependent manner, which was completely inhibited by 0.1 M lactose, the competitive inhibitory sugar for this protein. Mucin purified from highly metastatic LS-Lim6 human colon cancer cells bound galectin-3 to a 2-fold greater extent than mucin from low-metastatic parental cell line LS174T. Desialylation increased binding to mucin >4-fold. Mucin purified from LS-B colon cancer cells is fully glycosylated and bound >40-fold more galectin-3 than mucin purified from clonal cell line LS-C, which produces mucin lacking peripheral carbohydrate structures. Endogenous galectin-3 was detected by Western analysis in all cell lines, and its expression was related to mucin production and metastatic capacity. When serum from a patient with metastatic colorectal cancer was chromatographed on Superose 6, >70% of galectin-3 ligand was identified as circulating mucin. Colon cancer mucin is a newly identified ligand for galectin-3, and binding of galectin-3 to mucins depends on peripheral carbohydrate structures. Binding of this endogenous lectin to mucins; may influence cellular interactions that play a role in colon cancer metastasis.

Adenocarcinoma↗
PubMed1996

Interactions between galectin-3 and Mac-2-binding protein mediate cell-cell adhesion.

Galectin-3 is a beta-galactoside-specific lectin implicated in diverse processes involved in cellular interactions. Recently, the Mac-2-binding protein, a heavily N-glycosylated secreted protein with a subunit Mr of 97,000, was identified as its ligand. The present study characterizes the interaction between galectin-3 and Mac-2-binding protein in whole cells and measures their relative expression levels. Incubation of A375 cells with affinity-purified Mac-2-binding protein resulted in its binding to galectin-3 on the cell surface in a specific carbohydrate-dependent manner. Mac-2-binding protein also induced homotypic cell aggregation, which was inhibited by lactose or Fab' fragments of an anti-galectin-3 antibody. Northern blotting analysis revealed differences in the transcriptional regulation of galectin-3 and Mac-2-binding protein. These results provide the first direct evidence for a Mac-2-binding protein function and suggest that it may play a role in tumor cell embolization during metastasis through interaction with galectin-3.

Antigens, Differentiation↗
PubMed1996

Tumor cell autocrine motility factor is the neuroleukin/phosphohexose isomerase polypeptide.

To date, the structure of the autocrine motility factor (AMF), a tumor-secreted cytokine which stimulates cell migration in vitro and metastasis in vivo, is unknown. Here, AMF secreted by Gc-4 PF murine fibrosarcoma into a protein-free conditioned media was isolated, purified, and microsequenced. The results demonstrate that AMF is the previously cloned cytokine and enzyme designated as neuroleukin, and phosphohexose isomerase (PHI), which has been independently implicated in cell motility, and to be a cancer progression marker. PHI catalyzes isomerization of glucose 6-phosphate to fructose 6-phosphate and is specific for both sugars. Murine AMF exhibits the enzymatic properties of PHI and rabbit heart PHI-stimulated mouse fibrosarcoma cells' motility similar to those of the endogenous AMF. Specific PHI inhibitors (carbohydrate phosphates) inhibited enzymatic activity and AMF-induced cell motility.

Amino Acid Sequence↗